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F Bischoff

Publications and source records attributed to F Bischoff.

At least 19 recordsLinked to original sources
PubMed2006

Synthesis and biodistribution of [11C]R107474, a new radiolabeled alpha2-adrenoceptor antagonist.

R107474, 2-methyl-3-[2-(1,2,3,4-tetrahydrobenzo[4,5]furo[3,2-c]pyridin-2-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one, was investigated using in vitro and in vivo receptor assays and proved to be a potent and relatively selective alpha(2)-adrenoceptor antagonist. Performed assays in vitro were inhibition of binding to a large number of neurotransmitter receptor sites, drug receptor binding sites, ion channel binding sites, peptide receptor binding sites, and the monoamine transporters in membrane preparations of brain tissue or of cells expressing the cloned human receptors. The compound has subnanomolar affinity for halpha(2A)- and halpha(2C)-adrenoceptors (K(i) = 0.13 and 0.15 nM, respectively) and showed nanomolar affinity for the halpha(2B)-adrenoceptors and 5-hydroxytryptamine(7) (h5-HT(7)) receptors (K(i) = 1 and 5 nM, respectively). R107474 interacted weakly (K(i) values ranging between 81 and 920 nM) with dopamine-hD(2L), -hD(3) and -hD(4), h5-HT(1D)-, h5-HT(1F)-, h5-HT(2A)-, h5-HT(2C)-, and h5-HT(5A) receptors. The compound, tested up to 10 microM, interacted only at micromolar concentrations or not at all with any of the other receptor or transporter binding sites tested in this study. In vivo alpha(2A)- and alpha(2C)-adrenoceptor occupancy was measured by ex vivo autoradiography 1h after subcutaneous (sc) administration of R107474. It was found that R107474 occupies the alpha(2A)- and alpha(2C)-adrenoceptors with an ED(50) (95% confidence limits) of 0.014 mg/kg sc (0.009-0.019) and 0.026 mg/kg sc (0.022-0.030), respectively. Radiolabeled 2-methyl-3-[2-([1-(11)C]-1,2,3,4-tetrahydrobenzo[4,5]furo[3,2-c]pyridin-2-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one ([(11)C]R107474) was prepared and evaluated as a potential positron emission tomography (PET) ligand for studying central alpha(2)-adrenoceptors. [(11)C]R107474 was obtained via a Pictet-Spengler reaction with [(11)C]formaldehyde in 33 +/- 4% overall decay-corrected radiochemical yield. The total synthesis time was 55 min and the specific activity was 24-28 GBq/micromol. The biodistribution of [(11)C]R107474 in rats revealed that the uptake of [(11)C]R107474 after in vivo intravenous administration is very rapid; in most tissues (including the brain) it reaches maximum concentration at 5 min after tracer injection. In agreement with the known distribution of alpha(2)-adrenoceptors in the brain, highest uptake of radioactivity was observed in septum (3.54 +/- 0.52 ID/g, 5 min pi) and entorhinal cortex (1.57 +/- 0.10 ID/g, 5 min pi). Tissue/cerebellum concentration ratios for septum (5.38 +/- 0.45, 30 min pi) and entorhinal cortex (3.43+/-0.24, 30 min pi) increased with time due to rapid uptake followed by a slow washout. In vivo blocking experiments using the non-selective alpha(2)-adrenoceptor antagonist mirtazapine demonstrated specific inhibition of [(11)C]R107474 binding in selective brain areas. The receptor binding profile of mirtazapine is reported and the selectivity of inhibition of binding is discussed. These results suggest that [(11)C]R107474 deserves further investigation as a potential radioligand for studying alpha(2)-adrenoceptors using PET.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2003

Preimplantation genetic diagnosis for a known cryptic translocation: follow-up clinical report and implication of segregation products.

This report describes preimplantation genetic diagnosis (PGD) of a couple with a known paternally-derived balanced cryptic translocation 46,XY.ish t(2q;17q)(210E14-,B37c1+;B37c1-,210E14+) in embryos from a couple who previously had a child with severe mental retardation and was previously described in this journal [Bacino et al., 2000]. This child inherited the unbalanced product of translocation from her father: 46,XX.ish der(2)t(2q;17q)pat(210E14-,B37c1+). The couple desired a normal offspring and sought PGD to avoid clinical pregnancy termination. They were treated three times with in vitro fertilization followed by PGD. Two sequential FISH hybridizations were performed. In the first hybridization, telomeric probes to 2q and 17q and a chromosome 17 centromere probe were employed. The second hybridization screened for maternal age-related aneuploidy (X,Y,13,18,21). Of the 18 informative embryos, only 4 (22%) were normal. The remaining 12 (67%) were abnormal; most with unbalanced products (10/12) from the paternally-derived rearrangement. The most frequent mode of segregation observed for this cryptic translocation was adjacent-1 (7/18, 39%). This suggests cryptic translocations are amenable to PGD and, as are traditional translocations, demonstrate higher frequencies of unbalanced segregants than the empiric risk of 10-15% observed at amniocentesis or chorionic villus sampling. Thus, cryptic translocations presumably behave like overt translocations, in that PGD must be performed on a relatively large number of embryos to assure even 2-3 transferable embryos.

Chromosomes, Human, Pair 17↗
PubMed2001

Arabidopsis thaliana Rop GTPases are localized to tips of root hairs and control polar growth.

Plants contain a novel unique subfamily of Rho GTPases, vital components of cellular signalling networks. Here we report a general role for some members of this family in polarized plant growth processes. We show that Arabidopsis AtRop4 and AtRop6 encode functional GTPases with similar intrinsic GTP hydrolysis rates. We localized AtRop proteins in root meristem cells to the cross-wall and cell plate membranes. Polar localization of AtRops in trichoblasts specifies the growth sites for emerging root hairs. These sites were visible before budding and elongation of the Arabidopsis root hair when AtRops accumulated at their tips. Expression of constitutively active AtRop4 and AtRop6 mutant proteins in root hairs of transgenic Arabidopsis plants abolished polarized growth and delocalized the tip-focused Ca2+ gradient. Polar localization of AtRops was inhibited by brefeldin A, but not by other drugs such as latrunculin B, cytochalasin D or caffeine. Our results demonstrate a general function of AtRop GTPases in tip growth and in polar diffuse growth.

Arabidopsis↗
PubMed2001

Synthesis and pharmacology of 3-isoxazolol amino acids as selective antagonists at group I metabotropic glutamic acid receptors.

Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid ligands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (iGluRs), the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid [HIBO, (RS)-4] so far known typically interact with iGluRs as well as metabotropic Glu receptors (mGluRs). We here report the synthesis and pharmacology of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 was shown to be an antagonist at group I mGluRs. The effects of 9 were shown to reside exclusively in (S)-9 (K(b) = 30 microM at mGlu(1) and K(b) = 61 microM at mGlu(5)). The lower homologue of 9, compound 8, showed comparable effects at mGluRs, but 8 also was a weak agonist at the AMPA subtype of iGluRs. Like 9, the higher homologue, compound 10, did not interact with iGluRs, but 10 selectively antagonized mGlu(1) (K(b) = 160 microM) showing very weak antagonist effect at mGlu(5) (K(b) = 990 microM). The phenyl analogue 11 turned out to be an AMPA agonist and an antagonist at mGlu(1) and mGlu(5), and these effects were shown to originate in (S)-11 (EC(50) = 395 microM, K(b) = 86 and 90 microM, respectively). Compound 9, administered icv, but not sc, was shown to protect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments of the enantiomers were based on X-ray crystallographic analyses.

Amino Acids↗
PubMed2001

[Cause of death in patients with cirrhosis].

PURPOSE: Since 1970, the rate of death from cirrhosis has decreased progressively, in part thanks to better handling of complications (preventive and curative treatment of gastric bleeding, prevention of infections and treatment of ascitis). The goal of this study was to examine the evolution in causes of death among cirrhotics. METHODS: We identified all of the patients who died among those cirrhotics hospitalized at the Alençon Hospital during the period covered by the study, from January 1, 1993 to December 31, 1998. We examined the age of death of these cirrhotics, their causes of death, and also studied and compared this data with causes of death cited in the literature of the 1980s. Finally, we examined the prevalence of each cause of death in relation to the age of death of each patient. RESULTS: Our results show that 347 cirrhotics were hospitalized at the Alençon Hospital during the period covered by the study, and 186 of these patients died. These deaths resulted from hepatocarcinoma in 22% of cases, gastric bleeding in 12% of cases, and liver cell failure at a terminal stage in 21% of cases. In 31% of cases, the cause was unrelated to cirrhosis, and in 13% of cases the cause was unknown. The death rate from hepatocarcinoma increased according to the patients' age, while the death rate from gastric bleeding decreased according to age. CONCLUSION: We have noted, in comparison with Saunders in 1981 that there was a significant increase in extrahepatic causes of death and a significant decrease in deaths from liver cell failure. Percentages of the other causes of death do not show any variation, in spite of new techniques of detection and treatment.

Carcinoma, Hepatocellular↗
PubMed2000

Localization of AtROP4 and AtROP6 and interaction with the guanine nucleotide dissociation inhibitor AtRhoGDI1 from Arabidopsis.

The small GTPases of the Rho family play a key role in actin cytoskeletal organization. In plants, a novel Rho subfamily, called ROP (Rho of plants), has been found. In Arabidopsis, 12 ROP GTPases have been identified which differ mainly at their C-termini. To test the localization of two members of this subfamily (AtROP4 and AtROP6), we have generated translational fusions with the green fluorescent protein (GFP). Microscopic analysis of transiently transfected BY2 cells revealed a predominant localization of AtROP4 in the perinuclear region, while AtROP6 was localized almost exclusively to the plasma membrane. Swapping of the AtROP4 and AtROP6 C-termini produced a change in localization. As RhoGDIs are known to bind to the C-terminus of GTPases of the Rho family, we searched for Arabidopsis RhoGDI genes. We identified the AtRhoGDI1 gene and mapped it to chromosome 3. AtRhoGDI1 encodes a 22.5 kDa protein which contains highly conserved amino acids in the isoprene binding pocket and exhibits 29% to 37% similarity to known mammalian RhoGDI homologues. The AtRhoGDI1 gene was expressed in all tissues studied. Using the yeast two-hybrid system, we showed specific interaction of AtRhoGDI1 with both AtROP4 and AtROP6 as well as with their GTP-locked mutants, but not with a GTPase of the RAB family. Recombinant GST-AtRhoGDI1 could bind GFP-AtROP4 from transgenic tobacco BY2 cell extracts, confirming the interaction observed with the two-hybrid system.

Amino Acid Sequence↗
PubMed1999

GTP-binding proteins in plants.

GTP-binding proteins are found in all organisms. They are important switches that cycle between an active and an inactive state, ensuring vectorial flow of information on the expense of guanosine triphosphate (GTP). In this review, we discuss current progress in the molecular characterization and functional analysis of plant genes encoding heterotrimeric and small GTPases. An up-to-date list including all cloned plant GTPase genes is given and a systematic classification is proposed.

Animals↗
PubMed1997

At-GDI1 from Arabidopsis thaliana encodes a rab-specific GDP dissociation inhibitor that complements the sec19 mutation of Saccharomyces cerevisiae.

Rab GTPases play a central role in the control of vesicular membrane traffic. These proteins cycle between cytosolic and membrane-bound compartments in a guanine nucleotide-dependent manner, a process that is regulated by several accessory proteins. Of particular interest are the Rab guanosine nucleotide diphosphate dissociation inhibitor proteins (Rab-GDI) which bind to prenylated Rab GTPases, slow the rate of GDP dissociation and escort GDP bound Rab proteins to their target membranes and retrieve them after completion of their catalytic cycle. We have cloned from Arabidopsis thaliana a cDNA coding for the Rab guanosine diphosphate dissociation inhibitor (AtGDI1) by functional complementation of the Saccharomyces cerevisiae sec19-1 mutant. The Arabidopsis cDNA potentially encodes a 49850 Da protein which is homologous to yeast GDI (49%) and to other members of the Rab-GDI family (49-63%). Northern blot analysis indicates that the mRNA is expressed in all tissues examined. The existence of a plant homologue of the Rab-GDI family indicates that the basic vesicle traffic control machinery may be highly conserved in plants as it is in yeast and mammals.

Amino Acid Sequence↗
PubMed1995

Excitatory amino acid receptor ligands: asymmetric synthesis, absolute stereochemistry and pharmacology of (R)- and (S)-homoibotenic acid.

The (R)- and (S)-forms of 2-amino-3-(3-hydroxyisoxazol-5-yl)propionic acid (homoibotenic acid, HIBO) were synthesized, using (S)-BOC-phenylalanine as a chiral auxiliary and their absolute stereochemistry correlated with that of (R)-Br-HIBO. The enantiomeric excesses for (R)-HIBO (1) (> 99.5%) and (S)-HIBO (2) (99.5%) were determined using chiral HPLC. Whereas compounds 1 and 2 were equipotent inhibitors of the binding of [3H]glutamic acid in the presence of calcium chloride, 2 showed AMPA agonist activity and 1 very weak NMDA agonist activity.

Animals↗
PubMed1982

Tissue reaction to and fate of parenterally administered titanium dioxide. I. The intraperitoneal site in male Marsh-Buffalo mice.

In 32 male Marsh-Buffalo mice each receiving a saline suspension of 25 mg TiO2 intraperitoneally, four neoplasms appeared over the 18-month experimental period. During this time, four neoplasms appeared in 30 control mice receiving isotonic saline by the same injection route. A nonsignificant association of tumorigenesis with experimental treatment indicated a lack of carcinogenic potential for TiO2 and is discussed in terms of the local tissue reaction in the mice that received the TiO2. Focal deposits of dose material rather than a diffuse distribution were found on the intraperitoneal wall and muscles as well as the gut. In some instances, TiO2 had migrated from the initial injection site. For the most part, no foreign-body reaction to TiO2 involving the presence of macrophages or characteristic capsular connective tissue formation was demonstrated, although a dose deposit attached to the peritoneum by a transparent membrane was observed. In one mouse, chronic myositis developed in muscle tissue containing a large amount of dose material.

Animals↗
PubMed1981

Long-term estrogenization in mammals. IV. Body, adrenal, and testes weights; polydipsia; food intake; vasopressin administration; and serum corticosterone levels in estrogenized male Evans rats.

In three experiments, the initial body weight losses after estrogenization were maintained or lagged the weight gains of the controls by the same amount over 61, 138, and 336 days, respectively. The mean serum corticosterone level of the controls was 56% that of the estrogenized rats 341 days after estrogenization. Water consumption (mg/kg b.w.) approximated 150% that of the controls several weeks following estrogenization, remaining elevated until the end of the experiment. Estrogen treatment produced a higher level of water intake in a few rats similar to that previously observed for mice. During the experimental period for water measurement, food consumption (g/kg b.w.) approximated 115% that of the controls. Gnawing and food-spilling behavior was observed in some of the estrogenized rats. Following vasopressin administration, food intake was lowered the first and second days in one estrogenized group; water intake was lowered the first day in the three control and estrogenized groups. In contrast to studies with Marsh mice, estrogenization did not produce bladder damage in Evans rats, but two showed tubular calcification in the kidneys.

Adrenal Glands↗
PubMed1980

Long-term estrogenization in mammals. II. Environmental influences of housing conditions upon estrogen-induced polydipsia and food intake in Marsh mice.

Estrogen-induced polydipsia was influenced by environmental conditions in which Marsh mice were housed in plastic cages with bedding or in metal cages having grilled floors and no bedding. Increases in this polydipsia with metal-cage housing were reversed upon return to plastic. The increases over controls as ml/kg body weight ranged from 40 to 250%. After an initial fall in food consumption following estrogenization, controls and estrogenized mice consumed nearly the same amount of food/mouse but 10% more for the estrogenized mice on a g/kg body-weight basis. Increased food consumption for controls and estrogenized mice following the change from plastic to metal cages was attributed to compensation for increased loss of body heat. Whether in plastic or metal cages, core temperatures of controls were higher than those of estrogenized mice; both groups had relatively higher temperatures in the metal cages. The older mice in metal cages developed a gnawing pattern wasting food. In five experiments with males, body-weight losses following estrogenization were maintained 43 to 70 days but recovered in 2 of 4 experiments with females under comparable conditions.

Animals↗
PubMed1980

Long-term estrogenization in mammals. III. Vasopressin and calcitonin in the regulation of water intake in estrogenized Marsh mice.

During the increasing polydipsia following estrogenization, vasopressin administration produced increasing antidiuretic effects demonstrating that renal receptor sites remained functional. The antidiuretic effect in the controls was less than in the estrogenized mice. An antidiuretic effect with calcitonin was demonstrated in the controls and in one experiment in the estrogenized mice but not in another with a high standard error for water intake. A decrease in food intake for the estrogenized mice the first day after vasopressin administration was of doubtful significance. A significant decrease in food intake in the control and estrogenized mice was demonstrated for calcitonin. The effects of the vehicles used for hormone administration on water and food intake necessitated a correction in some instances. As previously observed in estrogenized mice, bladder pathology preceded kidney pathology in additional experiments.

Animals↗
PubMed1979

Long-term estrogenization in mammals. I. Histopathology of kidney, bladder, adrenals, and gonads; polydipsia; body weight; and serum levels of corticosterone and testosterone in estrogenized Marsh mice.

Single, sublethal, long-acting doses of estrone or estradiol cypionate produced the following histologic, behavioral, and blood chemistry effects in Marsh mice: (a) Bladder pathology developed following estrogen-induced polydipsia but was not consistently associated with kidney damage. (b) This polydipsia was more intense (a maximum of 250% over control intake) when the housing was in metal cages with floor screens than in plastic cages with bedding. Water intake of control mice was unaffected by housing changes. (c) Comparing litter-mate 2.5-month-old males and females, body weight loss following estrogen administration was transient with the females. With males, initial weight losses as compared with weight gains in the controls were demonstrated over a 20-week period. (d) Estrogenization markedly increased corticosterone and decreased testosterone serum levels with a significant negative correlation for these levels in the estrogenized mice. A significant positive correlation was also observed between testosterone levels and testis weights in the estrogenized mice.

Adrenal Glands↗
PubMed1979

Short- and long-term effects of graduated doses of DL-6-OH-DOPA upon marsh mice.

The lethal effects in Marsh mice for a range of DL-6-OH-DOPA levels were ascertained and exceeded those previously reported for 6-OH-DA under comparable conditions. The addition of vitamin "C" to the 6-OH-DOPA solution given intraperitoneally increased the lethal effect, as did the intraperitionel route of injection over that of the subcutaneous. Increased water consumption developed the fourth day for those surviving toxic levels of 6-OH-DOPA given subcutaneously as compared with controls. For all mice initially surviving administration of 6-OH-DOPA, tumorigenesis and long-term survival were of the same order as that of the controls. The toxicity of 6-OH-DOPA relating to ferric heme formation more likely involves metmyoglobin than methemoglobin. The combination of direct damage to sympathetic adrenergic cardiac innervation and metmyoglobin formation appears sufficient to account for the lethal effects of 6-OH-DOPA.

Age Factors↗
PubMed1978

Species differences in blood serum reserves for cholesterol solubilization.

The capacity of male human, rat, and guinea pig sera to solubilize cholesterol was measured by in vitro equilibration. Evaporation, adsorption by filter paper and/or cholesterol, and protein denaturation were controlled by measuring serum protein and albumin along with cholesterol contents. The uptake of cholesterol for the above groups was 23.1 +/- 1.2, 18.9 +/- 1.8, and 10.7 +/- 0.8 mg/100 ml, respectively. The percentage increases over initial serum cholesterol were 11.9 +/- 0.9, 18.7 +/- 2.0, and 35.1 +/- 2.7%, respectively. The uptake of cholesterol by serum per se without involvement of either releasing or target tissues appears to be an irreversible and protective solubility phenomenon; no cholesterol plates were deposited upon the undissolved solute or precipitated on addition of triglyceride to cholesterol-saturated serum. The omnivorous human and rat had a greater absolute reserve for solubilizing cholesterol, but the herbivorous guinea pig a greatly enhanced relative (% increase) reserve.

Animals↗